Novel 5-thio-B-D-xylopryanoside derivatives, preparation, method, pharmaceutical compositions containing them and their therapeutic use

ABSTRACT

The present invention relates to novel compounds of formula (I):  
                 
 
     in which:  
     R 1 , R 2  and R 3 , which are identical or different, are each independently:  
     a (C 1 -C 6 )alkyl group,  
     a pyridinyl group or  
     a group —CH 2 —NR 4 R 5 , in which R 4  and R 5  are each independently a hydrogen atom or a (C 1 -C 4 )alkyl group, or alternatively R 4  and R 5  form, with the nitrogen atom to which they are bonded, a pyrrolidinyl, piperidinyl, hexahydroazepinyl, morpholinyl or piperazinyl group,  
     with the proviso that at least one of the substituents R 1 , R 2  and R 3  is other than a (C 1 -C 6 )alkyl group,  
     and their salts, solvates and hydrates, especially those which are pharmaceutically acceptable.  
     These compounds are useful particularly for the treatment of disorders of the venous circulation.

[0001] The present invention relates to novel4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-β-D-xylopyranosidederivatives, to their use for the preparation of antithrombotic drugsand to the pharmaceutical compositions containing them. The inventionfurther relates to a method for the preparation of these compounds.

[0002] Patent EP 421 829 describes benzopyranone β-D-thioxylosides offormula (A):

[0003] in which:

[0004] X is O or S,

[0005] Y is especially a hydrogen atom or the group —COCH₃,

[0006] Ra is especially a (C₁-C₄)alkyl group and

[0007] Rb is in particular a hydrogen atom, a (C₁-C₄)alkyl group or ahalogen atom.

[0008] These compounds are useful in the treatment and prevention ofdiseases associated with circulatory disorders, especially as venousantithrombotics.

[0009] However, the compounds described in EP 421 829 are insufficientlysoluble, especially in physiologically acceptable solvents, to allowthem to be administered by injection. Thus they cannot be used in casesof emergency administration or on unconscious patients for whominjection is the only possible route of administration, or if it ispreferable for the sake of convenience to administer one of thesecompounds in association with other drugs by perfusion.

[0010] The present invention relates to novel4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-β-D-xylopyranosidederivatives with an antithrombotic activity. These compounds have a goodsolubility in the conventional physiologically acceptable solvents,especially injectable solutions. They can therefore be administered bothorally and by injection, especially intravenous injection.

[0011] According to one of its features, the invention therefore relatesto the compounds of formula (I):

[0012] in which:

[0013] R₁, R₂ and R₃, which are identical or different, are eachindependently:

[0014] a (C₁-C₆)alkyl group,

[0015] a pyridinyl group or

[0016] a group —CH₂—NR₄R, in which R₄ and R₅ are each independently ahydrogen atom or a (C₁-C₄)alkyl group, or alternatively R₄ and R₅ form,with the nitrogen atom to which they are bonded, a pyrrolidinyl,piperidinyl, hexahydroazepinyl, morpholinyl or piperazinyl group,

[0017] with the proviso that at least one of the substituents R₁, R₂ andR₃ is other than a (C₁-C₆)alkyl group,

[0018] and their salts, solvates and hydrates, especially those whichare pharmaceutically acceptable.

[0019] In the present description, (C₁-C₄)alkyl group is understood asmeaning a linear or branched, saturated hydrocarbon chain having from 1to 4 carbon atoms. Examples of (C₁-C₄)alkyl groups include methyl,ethyl, propyl, butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl and1,1-dimethylethyl groups. (C₁-C₆)alkyl group is understood as meaning alinear or branched, saturated hydrocarbon chain having from 1 to 6carbon atoms. Examples of (C₁-C₆)alkyl groups include those listed aboveand also pentyl and hexyl groups.

[0020] Salts are understood as meaning the addition salts obtained byreacting a compound of formula I, containing at least one basicfunctional group in its non-salified form, with a mineral or organicacid. Said addition salts will preferably be those which arepharmaceutically acceptable.

[0021] Hydrochloric, hydrobromic, phosphoric and sulfuric acids arepreferred among the mineral acids which are suitable for salifying abasic compound of formula I. Methanesulfonic and trifluoroacetic acidsare preferred among the organic acids which are suitable for salifying abasic compound of formula I.

[0022] The preferred compounds of formula (1) of the invention are thosein which:

[0023] R₁, R₂ and R₃, which are identical or different, are eachindependently:

[0024] a (C₁-C₄)alkyl group,

[0025] a pyridin-3-yl group or

[0026] a group —CH₂—NR₄R₅ in which R₄ and R₅ are each independently ahydrogen atom or a (C₁-C₄)alkyl group, or alternatively R₄ and R₅ form,with the nitrogen atom to which they are bonded, a pyrrolidinyl,piperidinyl or morpholinyl group,

[0027] with the proviso that at least one of the substituents R₁, R₂ andR₃ is other than a (C₁-C₄)alkyl group,

[0028] and their pharmaceutically acceptable salts, solvates andhydrates.

[0029] The compounds of formula (I) in which at least two of thesubstituents R, R₂ and R₃ are identical, and their pharmaceuticallyacceptable salts, solvates and hydrates, are also preferred compounds ofthe invention.

[0030] The compounds of formula (I) in which R₁, R₂ and R₃ areidentical, and their pharmaceutically acceptable salts, solvates andhydrates, are also preferred compounds of the invention.

[0031] According to another feature, the invention relates to a methodfor the preparation of the compounds of formula (I) which comprises thesteps consisting in:

[0032] 1) reacting a 5-thio-β-D-xylopyranoside derivative of formula(II):

[0033] in which:

[0034] either R′₁, R′₂ and R′₃ are identical and are a hydroxyl group,

[0035] or two of the substituents R′₁, R′₂ and R′₃ are identical and area hydroxyl group and the other substituent R′₁, R′₂ or R′₃ isrespectively —OC(O)R₁, —OC(O)R₂ or —OC(O)R₃, where R₁, R₂ and R₃ are asdefined for (I),

[0036] or one of the substituents R′₁, R′₂ and R′₃ is a hydroxyl groupand the other two substituents R′₁, R′₂ and R′₃ are respectively—OC(O)R₁, —OC(O)R₂ or —OC(O)R₃, where R₁, R₂ and R₃ are as defined for(I),

[0037] with an appropriate acid of formula (III):

[0038] or an appropriate acid halide of formula (IIIa):

[0039] in which Hal is a halogen atom, especially chlorine, fluorine orbromine and preferably chlorine, and R is R₁, R₂ or R₃ as defined for(I); and

[0040] 2) optionally converting the resulting compound of formula (I) toone of its salts.

[0041] The first step of the method of the invention is anesterification step, which can be carried out by the procedures wellknown to those skilled in the art.

[0042] Advantageously, this esterification step is carried out with theaid of a coupling agent such as a carbodiimide, for example1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI), preferably inthe presence of 1-hydroxybenzotriazole (HOBT).

[0043] The esterification reaction is generally carried out in ananhydrous solvent, for example dimethylformamide (DMF), pyridine ordichloromethane, in the presence of an aprotic base such astriethylamine, 4-dimethylaminopyridine (DMAP) or mixtures thereof.

[0044] The reaction is preferably carried out under a dry inertatmosphere, for example under a nitrogen or argon atmosphere, and in thepresence of a moisture trap such as a molecular sieve.

[0045] The reaction is advantageously carried out between roomtemperature and the reflux temperature of the solvent.

[0046] The second step of the method of the invention is a salificationstep, which is carried out by methods well known to those skilled in theart, the compounds of formula (I) being reacted with mineral or organicacids, especially those which are pharmaceutically acceptable, forexample hydrochloric acid, methanesulfonic acid or trifluoroacetic acid.

[0047] The acids (III) and acid halides (IIIa) are commerciallyavailable compounds or are prepared by conventional methods.

[0048] The compound of formula (II) in which R′₁=R′₂=R′₃=OH, hereaftercalled compound I.1, is described in patent EP421 829. The othercompounds of formula (II) can be obtained from the compound II.1 byreaction with an acid or an acid halide of formula (III) or (IIIa), inwhich the groups R₁, R₂ and R₃ are optionally protected as indicatedbelow.

[0049] The compounds of formula (II) can also be obtained from thestannylene-type derivative of formula (IV):

[0050] in which Bu denotes butyl, following the procedure described e.g.in J. Org. Chem. 1991,56,7015.

[0051] The ester-type functional groups of the compound (II) can beobtained selectively by reacting one or two equivalents of appropriateacylating agents of formula (IIIa) with the compound of formula (IV).

[0052] If the radicals R₁, R₂ and/or R₃ contain free amine groups, theyare preferably protected with protecting groups so that the desiredcompounds of formula (I) can be obtained.

[0053] The protection and deprotection reactions are carried out by thetechniques well known to those skilled in the art. Thetert-butoxycarbonyl group, which is cleavable in an acid medium, willadvantageously be used as the protecting group for the amine group.

[0054] In the remainder of the description, the compounds of formula(II) protected in this way will be called compounds (I′). They areobtained by reacting the compounds of formula (II) with an acid or anacid halide of formula (III) or (IIIa) in which the groups R₁, R₂ and R₃are protected.

[0055] The compounds according to the invention were the subject ofpharmacological studies.

[0056] The antithrombotic activity of the compounds according to theinvention was studied in vivo in the rat by means of a test whichreproduces venous thrombosis.

[0057] The oral activity was studied according to the protocol describedin Thromb. Haemost. 1992, 67(1), 176-179. The intravenous or oralactivity was studied according to the following operating protocol:

[0058] The experiments are performed on non-fasted Wistar male ratsweighing 250 to 280 g, divided into groups of 10 animals each. The testproducts are administered either orally (tubage) dissolved or suspendedin isotonic solution, or by intravenous injection dissolved in isotonicsolution. The concentration of the compounds is calculated so that theamount of solution absorbed is 2 ml/kg by oral administration and 1ml/kg by intravenous injection. Thrombosis is induced at a time T (2, 4or 8 hours) after the administration of the product, and the thrombusformed is removed and weighed. To induce this thrombosis, a venousstasis is -created under hypercoagulation according to the techniquedescribed by WESSLER (J. Applied Physiol. 1959, 943-946), thehypercoagulating agent used being a solution of activated factor X (Xa)having a concentration of 7.5 nKat/kg, supplied by Biogenic. Theactivity of the test compounds was checked at different doses after theyhad been administered either orally (p.o.) or intravenously (iv.). Thethrombosis was induced 4 hours or 8 hours after oral administration ofthe compound and 2 hours after intravenous administration of thecompound. For doses varying between 8 and 17 mg p.o., the percentageinhibition obtained after 4 hours, calculated relative to the weight ofa thrombus obtained in the absence of active principle in the isotonicsolution, varied between 40 and 99%. For doses eFu varying between 5 and7 mg i.v., the percentage inhibition obtained after 2 hours variedbetween 40 and 95%.

[0059] These results show that the compounds according to the inventionexhibit an antithrombotic activity, particularly on venous thrombosis,by both oral and intravenous administration.

[0060] By way of comparison, the compounds described in EP421 829 areinsoluble in isotonic solution and cannot therefore be administeredintravenously.

[0061] The present invention therefore relates to the compounds offormula (I) according to the invention, and their pharmaceuticallyacceptable salts, solvates and hydrates, for use as drugs. The compoundsof formula (I), or one of their pharmaceutically acceptable salts,solvates or hydrates, may be used for the preparation of anantithrombotic drug intended in particular for the treatment orprevention of disorders of the venous circulation and especially forcorrecting certain hematological parameters perceptible in the venoussystem.

[0062] The present invention therefore further relates to pharmaceuticalcompositions containing a compound of formula (I) or one of itspharmaceutically acceptable salts, solvates or hydrates. Thesepharmaceutical compositions generally contain suitable excipients. Saidexcipients are chosen according to the desired pharmaceutical form andthe desired mode of administration, particularly oral administration oradministration by injection.

[0063] These pharmaceutical compositions are prepared by theconventional methods well known to those skilled in the art. Forexample, the compounds according to the invention can be formulated withphysiologically acceptable excipients to give an injectable form fordirect use, an injectable form to be prepared immediately before use, ora solid form for oral administration, for example a gelatin capsule or atablet.

[0064] By way of example, an injectable form can preferably be preparedby the lyophilization of a sterilized filtered solution containing thecompound according to the invention and a soluble excipient in anecessary and sufficient amount to give an isotonic solution after theaddition of injectable water immediately before use. An oral form willpreferably be presented in the form of a gelatin capsule containing thefinely ground or, preferably, micronized compound of the invention mixedwith excipients known to those skilled in the art, for example lactose,pregelatinized starch and magnesium stearate.

[0065] To obtain the desired therapeutic or prophylactic effect, eachunit dose can contain 25 to 500 mg of at least one compound according tothe invention.

[0066] In the Examples which follow, “preparation” denotes the Examplesdescribing the synthesis of intermediates, and “Example” denotes thosedescribing the synthesis of compounds of formula (I) according to theinvention. These Examples are intended to illustrate the invention andcannot in any way limit its scope. The melting points are measured on aKoffler bench and the nuclear magnetic resonance spectral values arecharacterized by the chemical shift calculated relative to TMS, by thenumber of protons associated with the signal, and by the shape of thesignal (s for singlet, d for doublet, t for triplet, q for quadruplet, mfor multiplet). The operating frequency and the solvent used areindicated for each compound.

[0067] In these Examples, the abbreviation DMSO denotes dimethylsulfoxide.

[0068] Preparation 1

[0069] N-Morpholinoacetic Acid, Compound III.1

[0070] a) Benzyl N-morpholinoacetate

[0071] 3 ml of morpholine are added under a stream of argon at roomtemperature to a solution of 5.03 g of benzyl 2-bromoacetate in 75 ml oftetrahydrofuran. A white precipitate forms instantly. The mixture isthen stirred for 17 hours. The white salt which has precipitated isfiltered off and washed with 50 ml of ethyl acetate. The filtrate iswashed successively with 50 ml of saturated aqueous sodium carbonatesolution, 50 ml of water and 50 ml of saturated aqueous sodium chloridesolution. The organic phase is dried over magnesium sulfate, filteredand evaporated and the residual yellow liquid is purified bychromatography on silica gel (eluent: ethyl acetate/hexane, 6/4, v/v).(Yield=64%)

[0072] b) N-Morpholinoacetic Acid

[0073] 325 mg of palladium on activated charcoal are added to a solutionof 3.25 g of benzyl N-morpholinoacetate in 100 ml of ethanol. Themixture is then stirred under a hydrogen atmosphere at room temperaturefor 17 hours. The catalyst is filtered off and rinsed with 2×50 ml ofmethanol. The filtrate is evaporated to give the expected product in theform of a white solid. (Yield =97%) M.p.=151-155° C.

[0074] The following compounds are synthesized in the same manner:

[0075] N-piperidinoacetic acid, compound III.2; m.p.=209-212° C.

[0076] N-pyrrolidinoacetic acid, compound III.3; m.p.=138-141° C.

[0077] N,N-diethylglycine, compound III.4; m.p.=131-133° C.

[0078] Preparation 2

[0079] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl3,4-di-O-acetyl-5-thio-β-D-xylopyranoside, compound II.2

[0080] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2,4-di-O-acetyl-5-thio-β-D-xylopyranoside, compound II.3

[0081] a) 4-Methyl-2-oxo-2H-1-benzopyran-7-yl3,4-di-O-(dibutylstannylene)-5-thio-β-D-xylopyranoside, compound IV

[0082] A suspension of 4 g of 4-methyl-2-oxo-2H-1-benzopyran-7-yl5-thio-β-D-xylopyranoside (compound II.1) and 6.14 g of dibutyltin oxidein 200 ml of methanol is stirred under reflux for 4 hours in around-bottom flask equipped with a Soxhlet apparatus fitted with acartridge containing a 4 Å molecular sieve. After filtration of thereaction mixture, the solvent is evaporated off under reduced pressure.The resulting compound IV is used as such in the next steps.

[0083] b) A solution of 1.9 g of acetyl chloride in 20 ml of dioxane isadded dropwise to a suspension of 6.25 g of compound IV in 200 ml ofdioxane. After 2 hours at 30° C., the reaction mixture is filtered andthe solvents are evaporated off under reduced pressure. 1.5 g ofcompound II.2 (34%) and 660 mg of compound 11.3 (14%) are separated outby chromatography on silica gel (cyclohexane/ethyl acetate, 45/55, v/v).

[0084] Compound II.2: m.p. =169° C.; [α]_(D) ²=−162° (c=0.2, CHCl₃)

[0085] Compound II.3: ¹H NMR (300 MHz, DMSO): 7.70 (d, 1H); 7.17 (d,1H); 7.00 (dd, 1H); 6.28 (s, 1H); 5.75 (d, 1H, J₁₂=9 Hz); 5.16 (t, 1H);4.77 (m, 1H); 3.62 (m, 1H); 2.84 (m, 2H); 2.40 (s, 3H); 2.00 (s, 3H);1.96 (s, 3H)

[0086] Preparation 3

[0087]4-Methyl-2-oxo-2H-1-benzopyran-7-yl4—O-(2,2-dimethylpropanoyl)-5-thio-β-D-xylopyranoside, compound II.4

[0088] 19.575 g of trimethylacetyl chloride are added dropwise to asuspension of 41 g of compound IV obtained in PREPARATION 2 in 800 ml ofdioxane. After 2 hours at 30° C., the reaction mixture is filtered. Thefiltrates are taken up in ethyl acetate, washed with water and thendried over magnesium sulfate. The solvents are evaporated off underreduced pressure and the residue obtained is purified by chromatographyon a silica gel column (eluent: cyclohexane/ethyl acetate, 55/45, v/v).(Yield=59%)

[0089] M.p.=160° C.; [α]_(D) ²³=−97° (c=0.5, CH₃OH)

[0090] Preparation 4

[0091] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl4—O-acetyl-5-thio-β-D-xylopyranoside, compound II.5

[0092] 0.57 ml of acetyl chloride is added under an inert atmosphere toa solution of 4.4 g of compound IV obtained in PREPARATION 2 in 20 ml ofdichloromethane, a further 0.2 ml being added after stirring for 5hours. The reaction mixture is stirred for 3 days. After filtration, thecompound 11.5 is obtained. (Yield =61%)

[0093] M.p.=210° C.; [α]_(D) ²²=−68° (c=0.48, DMSO)

EXAMPLE 1

[0094] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2,3,4-tri-O-[(dimethylamino)acetyl]-5-thio-β-D-xylopyranoside

[0095] 2 ml of triethylamine, 2.84 g of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI), 0.56 g of4dimethylaminopyridine (DMAP), 30 ml of a 0.5 M solution of1-hydroxybenzotriazole hydrate (HOBT) in DMF and 1.53 g ofN,N-dimethylglycine are added successively under an argon atmosphere andin the presence of a 3 Å molecular sieve to a solution of 1 g of4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-β-D-xylopyranoside (compoundII.1) in 25 ml of dimethylformamide (DMF). The reaction mixture is thenstirred for 18 hours. The precipitate is filtered off and rinsed with 30ml of ethyl acetate. The filtrate is concentrated and the residualorange oil is taken up in 100 ml of water and 15 ml of triethylamine.The aqueous phase is extracted with ethyl acetate (100 ml+50 ml). Theorganic phases are combined and washed with 50 ml of water and then with50 ml of saturated aqueous sodium chloride solution. The organic phaseis then dried over magnesium sulfate, filtered and concentrated. Theresidual yellow solid is chromatographed on silica gel (eluent: ethylacetate/triethylamine 99/1, v/v, thendichloromethane/methanol/triethylamine, 9/1/0.1, v/v/v). The fractioncollected is evaporated and the residual yellowish solid foam is takenup in diethyl ether. The desired product is filtered off and rinsed withdiethyl ether. (Yield=72%)

[0096] M.p.=112-114° C.

[0097] The corresponding trihydrochloride (EXAMPLE 1A) is prepared byadding 7.5 ml of a 1 M solution of hydrogen chloride in diethyl ether toa solution of 0.7 g of the compound of EXAMPLE 1 in 3 ml of anhydrousmethanol at 0° C. A yellowish paste then forms instantly. The mixture issubsequently diluted with 5 ml of anhydrous diethyl ether, stirred at 0°C. for 1 hour and then concentrated to give a yellowish solid.

[0098] M.p.=196° C.; [α]_(D) ²⁹=−32° (c=0.55, CH₃OH)

[0099] EXAMPLES 2 to 5A shown in TABLE 1 below are prepared by followingthe same procedure starting from the corresponding acid (III), in thepresence or absence of HOBT. TABLE 1 (I)

EX- AMPLE R₁ M.p. (° C.) or ¹H NMR 2

M.p. = 209-212 2A

M.p. = 194 3

M.p. = 51-55 3A

M.p. = 187 4 —CH₂—N(CH₂CH₃)₂ ¹H NMR (300 MHz, CDCl₃): 7.50(d, 1H);6.96(2d, 2H); 6.18 (s, 1H); 5.54(m, 1H); 5.24(m, 3H); 3.28(s, 4H);3.24(s, 2H); 3.03(m, 1H); 2.58(m, 13H); 2.39 (s, 3H); 0.96(m, 8H) 4A—CH₂—N(CH₂CH₃)₂.HCl M.p. = 149 5

M.p. = 215 5A

M.p. = 198

EXAMPLE 6

[0100] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2,3,4-tri-O-(pyridin-3-ylcarbonyl)-5-thio-β-D-xylopyranoside

[0101] 4 g of compound II.1 and 11 g of nicotinoyl chloridehydrochloride in 50 ml of pyridine are stirred at room temperature for48 hours. The reaction mixture is filtered and the solvents areevaporated off. The residue obtained is washed with water and thenpurified by chromatography on silica gel using adichloromethane/methanol/aqueous ammonia mixture, 95/5/0.5, v/v/v, asthe eluent. The white powder obtained is dried under reduced pressure.[α]_(D) ²⁶=37° (c=0.6, CHCl₃)

EXAMPLE 7

[0102] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl3-O-[(dimethylamino)acetyl]-2,4-di-O-acetyl-5-thio-β-D-xylopyranoside

[0103] A solution of 620 mg of compound II.3 in 20 ml of dichloromethaneglib stabilized with amylene, in the presence of 563 mg of EDCI, 302 mgof N,N-dimethylglycine and 89 mg of DMAP, is refluxed for 1 hour. Thereaction mixture is then filtered. The filtrate is washed with asolution of ammonium chloride and sodium chloride and the organic phaseis then dried over magnesium sulfate. The solvents are evaporated offunder reduced pressure and the residue obtained is purified bychromatography on silica gel (eluent: toluene/isopropanol, 10/1, v/v).

[0104] (Yield=76%)

[0105] M.p.=214° C.

[0106]¹H NMR (300 MHz, DMSO): 6.00 (d, 1H, J2=8.4 Hz); 5.32 (2t, 2H);4.98 (m, 1H); 3.15 (m, 3H); 2.94 (m, 1H); 2.40 (s, 3H); 2.21 (s, 6H);2.00 and 1.92 (2s, 6H)

[0107] The corresponding methanesulfonate (EXAMPLE 7A) is obtained asfollows: 466 mg of the compound of EXAMPLE 7 are dissolved in 30 ml ofethyl acetate. A solution of 92 mg of methanesulfonic acid in 4 ml oftetrahydrofuran is added to this ethyl acetate solution. After one hour,the reaction mixture is filtered.

[0108] (Yield=79%)

[0109] M.p.=203° C.; [α]_(D) ^(21.5)=−56° (c=0.44, CHCl₃)

EXAMPLE 8

[0110] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2-O-[(dimethylamino)acetyl]-3,4-di-O-acetyl-5-thio-β-D-xylopyranoside

[0111] The compound of EXAMPLE 8 is prepared from the compound 11.2 by aprocedure analogous to that of EXAMPLE 7. (Yield =92%)

[0112] M.p.=102° C.

[0113]¹H NMR (300 MHz, DMSO): 6.02 (d, 1H, J₁₋₂=8.9 Hz); 5.4 (t, 1H);5.26 (t, 1H); 5.00 (m, 1H); 3.08 (m, 3H); 2.95 (m, 1H); 2.40 (s, 3H);2.21 (s, 6H); 2.01 and 1.99 (2s, 6H)

EXAMPLE 8A

[0114] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2—O-[(dimethylamino)acetyl]-3,4-di-O-acetyl-5-thio-β-D-xylopyranosidemethanesulfonate

[0115] The compound of EXAMPLE 8A is prepared by the same procedure asthat of EXAMPLE 7A. (Yield =76%)

[0116] M.p.=110° C.; [α]_(D) ²³=−44° (c=0.29, CHCl₃)

EXAMPLE 9

[0117] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2,3-bis-O-[(dimethylamino)acetyl]-4-O-(2,2-dimethylpropanoyl)-5-thio-β-D-xylopyranosidedimethanesulfonate

[0118] 2 g of compound II.4 are dissolved in 50 ml of dichloromethane inthe presence of a 4 Å molecular sieve. 3 g of EDCI, 0.6 g of DMAP and1.63 g of N,N-dimethylglycine are added. After stirring for 4 hours, thereaction mixture is filtered. The filtrate is washed with ammoniumchloride solution and with water and is then dried over magnesiumsulfate. The solvents are evaporated off under reduced pressure. Theresidue obtained is purified by chromatography on silica gel (eluent:dichloromethane/methanol, 10/1, v/v). 2.45 g of the compound obtainedare dissolved in 50 ml of anhydrous ethyl acetate, and a solution of 600μl of methanesulfonic acid in 13 ml of THF is then added dropwise. Afterstirring for 45 minutes, the precipitate is filtered off and dried.(Yield=69%)

[0119] M.p.=236° C.; [α]_(D) ²=−19° (c=0.41, DMSO)

EXAMPLE 10

[0120] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl4-O-acetyl-2,3-bis-O-[(dimethylamino)-acetyl]-5-thio-β-D-xylopyranosidedimethanesulfonate

[0121] A solution of 500 mg of compound II.5 in 20 ml of dichloromethaneis stirred under an inert atmosphere for 3 hours in the presence of 838mg of EDCI, 167 mg of DMAP and 450 mg of N,N-dimethylglycine. Thereaction mixture is then washed with water and the organic phase isconcentrated under reduced pressure. The residue is purified bychromatography on silica gel using a dichloromethane/methanol mixture,10/1, v/v, as the eluent. 490 mg of the compound obtained are taken upin 10 ml of ethyl acetate, and 135 μl of methanesulfonic acid in 2 ml oftetrahydrofuran are added. The precipitate is filtered off and driedunder reduced pressure. (Yield =50%)

[0122] M.p.=130° C.; [α]_(D) ²²=−14° (c=0.39, DMSO)

EXAMPLE 11

[0123] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2,3,4-tri-O-(aminoacetyl)-5-thio-β-D-xylopyranosidetris(trifluoroacetate)

[0124] a) 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2,3,4-tri-O-[(N-tert-butoxycarbonylamino)acetyl]-5-thio-β-D-xylopyranoside,compound I′.1

[0125] A suspension of 325 mg of compound II.1 in 15 ml ofdimethylformamide is heated until the solid has dissolved, and thencooled to room temperature. 578 mg of N-tert-butoxycarbonylglycine, 690mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and184 mg of dimethylaminopyridine are added, with stirring. The reactionmixture is kept under these conditions for 20 hours and thedimethylformamide is then evaporated off under reduced pressure. Theresidue is taken up in dichloromethane. This organic phase is washedsuccessively with 1N aqueous hydrochloric acid solution, sodiumhydrogencarbonate solution and saturated sodium chloride solution andthen dried over magnesium sulfate. The solvents in the organic phase areevaporated off under reduced pressure and the residue is then purifiedby chromatography on silica gel (toluene/ethyl acetate, 7/3, v/v).(Yield=80%)

[0126]¹H NMR (300 MHz, DMSO): 7.73 (d, 1H); 7.16 (m, 4H); 7.00 (dd, 1H);6.29 (s, 1H); 6.00 (d, 1H, J=8.8 Hz); 5.40 (t, 1H); 5.30 (t, 1H); 5.07(m, 1H); 3.68 (dd, 2H); 3.11 (t, 1H); 2.94 (dd, 1H); 1.38 (s, 9H)

[0127] b) 630 mg of compound I′. 1 are dissolved in 75 ml oftrifluoroacetic acid (TFA) and 25 ml of dichloromethane stabilized withamylene. The mixture is stirred at room temperature for 1 hour and thesolvents are then evaporated off under reduced pressure. The residue isprecipitated in diethyl ether and filtered off. This precipitate is thenpurified by chromatography on silica gel (water/acetonitrile/TFA,4/1/0.001, v/v/v). The fraction containing the deprotected amine islyophilized twice. (Yield=32%)

[0128] M.p.=136° C.; [α]_(D) ²⁴=−18° (c=0.155, CH₃OH)

EXAMPLE 11A

[0129] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2,3,4-tri-O-(aminoacetyl)-5-thio-β-D-xylopyranoside trihydrochloride

[0130] 40 ml of a 1 M solution of hydrogen chloride in diethyl ether areadded under an argon atmosphere at room temperature to a solution of 883mg of compound I′.1 in 5 ml of anhydrous ethanol. After stirring for 18hours, the white precipitate obtained is filtered off and then rinsedwith anhydrous diethyl ether. M.p. =180° C.; [α]_(D) ²⁶=−25° (c=0.42,CH₃OH)

EXAMPLE 12

[0131] 4-Methyl-2-oxo-2H-1-benzopyran-7-yl2,3,4-tri-O-[(methylamino)acetyl]-5-thio-β-D-xylopyranosidetrihydrochloride

[0132] The compound of EXAMPLE 12 is prepared from the compound II.1 andIN-(tert-butoxycarbonyl)-N-methylglycine by a procedure analogous tothat of

EXAMPLES 11 AND 11A

[0133] M.p.=195° C.; [α]_(D) ²³=−26° (c=0.36, CH₃OH)

What is claimed is:
 1. Compounds of formula (I):

in which: R₁, R₂ and R₃, which are identical or different, are eachindependently: a (C₁-C₆)alkyl group, a pyridinyl group or a group—CH₂—NR₄R₅, in which R₄ and R are each independently a hydrogen atom ora (C₁-C₄)alkyl group, or alternatively R₄ and R₅ form, with the nitrogenatom to which they are bonded, a pyrrolidinyl, piperidinyl,hexahydroampinyl, morpholinyl or piperazinyl group, with the provisothat at least one of the substituents R., R₂ and R₃ is other than a(C₁-C₆)alkyl group, and their salts, solvates and hydrates, especiallythose which are pharmaceutically acceptable.
 2. Compounds according toclaim 1, wherein R₁, R₂ and R₃ which are identical or different, areeach independently: a (C₁-C₄)alkyl group, a pyridin-3-yl group or agroup —CH₂—NR₄R₅ in which R₄ and R₅ are each independently a hydrogenatom or a (C₁-C₄)alkyl group, or alternatively R₄ and R₅ form, with thenitrogen atom to which they are bonded, a pyrrolidinyl, piperidinyl ormorpholinyl group, with the proviso that at least one of thesubstituents R₁, R₂ and R₃ is other than a (C₁-C₄)alkyl group. 3.Compounds according to claim 1 or 2, wherein at least two of thesubstituents R₁, R₂ and R₃ are identical.
 4. Compounds according toclaim 3, wherein R₁, R₂ and R₃ are identical.
 5. Method for thetreatment or prevention of disorders of the venous circulation,comprising administration of a therapeutically effective amount of acompound which is an antithrombotic agent, wherein said compound is acompound of formula (I):

in which: R₁, R₂ and R₃, which are identical or different, are eachindependently: a (C₁-C₆)alkyl group, a pyridinyl group or a group—CH₂—NR₄R₅, in which R₄ and R₅ are each independently a hydrogen atom ora (C₁-C₄)alkyl group, or alternatively R₄ and R₅ form, with the nitrogenatom to which they are bonded, a pyrrolidinyl, piperidinyl,hexahydroazepinyl, morpholinyl or piperazinyl group, with the provisothat at least one of the substituents R₁, R₂ and R₃ is other than a(C₁-C₆)alkyl group, and their salts, solvates and hydrates, especiallythose which are pharmaceutically acceptable.
 6. Pharmaceuticalcompositions in which a compound according to any one of claims 1 to 4is present as the active principle, in association with apharmaceutically acceptable excipient.
 7. Pharmaceutical compositionsaccording to claim 6 which are in injectable form.
 8. Method for thepreparation of a compound according to any one of claims 1 to 4 whichcomprises the steps consisting in: 1) reacting a5-thio-β-D-xylopyranoside derivative of formula (II):

in which: either R′₁, R′₂ and R′₃ are identical and are a hydroxylgroup, or two of the substituents R′₁, R′₂ and R′₃ are identical and area hydroxyl group and the other substituent R′₁, R′₂ or R′₃ isrespectively —OC(O)R₁, —OC(O)R₂ or —OC(O)R₃, where R₁, R₂ and R₃ are asdefined for (I), or one of the substituents R′₁, R′₂ and R′₃ is ahydroxyl group and the other two substituents R′₁, R′₂ and R′₃ arerespectively —OC(O)R₁, —OC(O)R₂ or —OC(O)R₃, where R₁, R₂ and R₃ are asdefined for (I), with an appropriate acid of formula (III):

or an appropriate acid halide of formula (Ia):

in which Hal is a halogen atom, especially chlorine, fluorine or bromineand preferably chlorine, and R is R₁, R₂ or R₃ as defined for (I); and2) optionally converting the resulting compound of formula (I) to one ofits salts.